Mycobacterium tuberculosis infection (Mtb) is the leading cause of death due to a single infectious agent and among the top ten causes of all human death worldwide. CD4 T cells are essential for resistance to Mtb infection, and for decades it has been thought that IFNg production is the primary mechanism of CD4 T cell-mediated protection. However, IFNg responses do not correlate with host protection, and several lines of evidence in from our lab have led us to reevaluate the dogmatic view that Th1 cells are the primary mechanism of control against pulmonary Mtb infection. Firstly, we have found that less differentiated CD4 T cells that produce relatively lower levels of IFNg in vivo are the most able to migrate into the lung and mediate control of Mtb infection. Secondly, we have found that the Th1 differentiation factors IL-12 and T-bet promote the formation of non-protective effector CD4 T cells that are incapable of entering into the lung and controlling Mtb infection, indicating that extensive Th1 differentiation is detrimental to protection in Mtb infection. Lastly, we have directly quantified the relative contribution of IFNg production by CD4 T cells in the control of Mtb infection and found that IFNg accounts for only 25% of CD4 T cell-dependent bacterial suppression in the lungs. In contrast to the limited role of Th1 responses to control of Mtb in the lungs, we find that CD4 T cell-derived IFNg is absolutely critical for control of Mtb infection in the periphery. This has led us to speculate that the major role for IFNg-producing CD4 T cells in Mtb infection is to prevent dissemination from the lungs to peripheral tissues or to control the growth of bacilli that have spread from the lungs. Therefore, our data have indicated that the properties of CD4 T cells that mediate control of pulmonary Mtb infection remain poorly understood. This has led us to search for novel CD4 T cell effector molecules that are required for resistance to pulmonary tuberculosis. To this end, we have shown that the TNF superfamily molecule CD153 is required for control of pulmonary Mtb infection by CD4 T cells. In Mtb infected mice, CD153 expression is highest on Mtb-specific Th1 cells in the lung tissue parenchyma, but its induction does not require Th1 polarization. CD153 deficient mice develop high pulmonary bacterial loads and succumb early to Mtb infection. Importantly, CD4 T cell expression of CD153 was critical for their host protective capacity. In macaques, CD153 expression is higher on Ag-specific CD4 T cells in the airways compared to blood, and the frequency of Mtb-specific CD153-expressing CD4 T cells inversely correlates with bacterial loads in granulomas. In humans, CD153 defines a subset of highly polyfunctional Mtb-specific CD4 T cells that are much more abundant in individuals with controlled latent Mtb infection compared to those with active TB. Thus, CD4 T cell-derived CD153 is a major immune mediator of host protection against pulmonary Mtb infection. Tracking CD153 expressing CD4 T cells may be valuable for the evaluation of Mtb vaccine candidates in clinical trials or animal model studies. CD153 may also be an important target for host-directed therapies for the treatment of tuberculosis.